The overall goal of this Program Project is to translate recent advances in the understanding of the molecular pathogenesis of cancer and the mechanisms of programmed cell death (apoptosis) into new cancer treatments. This Program Project is a logical development of the scientific collaboration of a group of investigators with major interests in studying apoptotic mechanisms and restoring the cancer cell apoptotic pathway. These investigators have complementary expertise in the areas of clinical trial design, clinical trials in gene transfer, vector technology, experimental radiation research, biochemistry, molecular biology, tumor suppressor genes, cell biology, and animal models. The projects are (1) Induction of Radiation Sensitivity and Apoptosis in Human Cancer Cells By Restoration of Wildtype p53 Expression, (2) Fas/FasL Interations in p53/radiation-induced Apoptosis, and (3) Strategies for Cell Death Manipulation in Cancer. The Cores are (A) Administration, (B) Laboratory Services, and (C) Informatics. The Program combines a clinical trial with laboratory research projects. The Projects are highly integrated so that the research in one project will advance the goals of the other projects and so there will be a bidirectional flow of information to generate new hypotheses. The overall goal of the Program Project is to test the hypothesis that restoration of critical gene function in the cancer cell can mediate therapeutic effects. The major emphasis in the Program Project is on apoptosis-related genes. The therapeutic potential of current vectors will be optimized, apoptotic mechanisms and their interaction with ionizing radiation will be studied, and new gene targets with therapeutic potential will be identified. The studies included in the Program Project could lead to cancer treatments targeted to specific genetic lesions in the cancer cell, thus representing novel mechanisms of action that could complement existing therapies.